RESUMEN
BACKGROUND: Salvianolic acid B (SAB) is one of the main active ingredients of Salvia Miltiorrhiza. It has significant skin anti-aging, whitening, and sun protection properties. AIMS: The study aimed at studying the mechanism underlying the effect of salvianolic acid Bon collagen synthesis, which has good anti-aging efficacy and modulates microcirculation. METHODS: This study employed available public databases, bioinformatics methodologies, and the inverse docking approach to explore the effectiveness of SAB in the regulating collagen synthesis, and then used an human dermal fibroblast (HDF)- Human dermal microvascular endothelial cell (HDMEC) in vitro model to validate the predicted mechanism of SAB in influencing collagen synthesis. RESULTS: The results showed that NO production in SAB-treated HDMEC-conditioned medium was increased compared to that in control media, and the same tendency was also observed for growth factor production. SAB also upregulated HDMEC cellular eNOS and VEGF. When SAB-treated HDMEC conditioned medium was transferred to HDFs, the expression of collagen I, collagen III, and elastin in HDFs was upregulated and MMP-1 was downregulated. CONCLUSIONS: The results show that SAB regulates collagen through the HDMEC-HDF pathway. Furthermore, the mechanisms might be closely related to the microcirculation factors NO and VEGF.
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Fibroblastos , Factor A de Crecimiento Endotelial Vascular , Benzofuranos , Células Cultivadas , Colágeno/metabolismo , Medios de Cultivo Condicionados/metabolismo , Células Endoteliales , Humanos , Piel , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Developing dermatitis therapeutics has been faced with challenges including adverse effects of topical steroid and high cost of new developing drugs. Here, we found the expression levels of dopamine receptor D2 is higher in skin biopsies of dermatitis patients and an oxazolone-induced animal model of dermatitis. We used perphenazine, an FDA-approved dopamine receptor antagonist to determine the therapeutic effect. Two different animal models including 12-o-tetradecanoylphorbol-13-acetate (TPA) and oxazolone (OXA)-induced dermatitis were employed. TPA and OXA-mediated ear swelling was attenuated by perphenazine. Moreover, perphenazine inhibited infiltrated mast cells into lesion area. We found levels of serum IgE, histamine and cytokines are decreased in mice cotreated with perphenazine and OXA compared to OXA-treated mice. Overall, this is a first study showing that the FDA-approved, anti-psychotic drug, perphenazine, alleviates animal models of dermatitis.
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Dermatitis Alérgica por Contacto/tratamiento farmacológico , Antagonistas de Dopamina/uso terapéutico , Perfenazina/uso terapéutico , Animales , Citocinas/metabolismo , Dermatitis Alérgica por Contacto/etiología , Antagonistas de Dopamina/farmacología , Inmunoglobulina G/metabolismo , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Células 3T3 NIH , Oxazolona/toxicidad , Perfenazina/farmacología , Acetato de Tetradecanoilforbol/toxicidad , Células Th2/efectos de los fármacos , Células Th2/inmunologíaRESUMEN
Metformin, a potent AMPK activator is the most commonly used drug for diabetes. According to recent reports, metformin lowers the risk of diabetic complications and inflammatory diseases. We found the expression levels of AMPK subunits including PRKAA1, PRKAA2, PRKAB1 and PRKAB2 are decreased in skin biopsies of dermatitis patients from multiple datasets. Interestingly, metformin treatment ameliorates dermatitis symptom in animal model of dermatitis using O-tetradecanoylphorbol-13-acetate (TPA). Especially, the levels of epidermis and dermis thickness were decreased by metformin. We found NFκB activity as well as of gene expression associated with collagen synthesis are attenuated by metformin treatment. These results suggest that metformin treatment alleviates animal model of dermatitis.
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Proteínas Quinasas Activadas por AMP/efectos de los fármacos , Dermatitis/tratamiento farmacológico , Activadores de Enzimas/farmacología , Metformina/farmacología , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Colágeno/metabolismo , Dermatitis/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Masculino , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Piel/efectos de los fármacos , Piel/patología , Acetato de TetradecanoilforbolRESUMEN
Cellular metabolism is one of the crucial factors to regulate epigenetic landscape in various cells including immune cells, embryonic stem cells and hair follicle stem cells. Dermal papilla cells (DP) interact with epithelial stem cells to orchestrate hair formation. Here we show that active DP exhibit robust aerobic glycolysis. We observed decrease of signature genes associated with hair induction by DP in presence of low glucose (2 mM) and glycolysis inhibitors. Moreover, hair shaft elongation was attenuated by glycolysis inhibitors. Interestingly, excessive glucose is able to increase the expression of hair inductive genes and elongation of hair shaft. We also observed glycolysis-mediated histone acetylation is increased and chemical inhibition of acetyltransferase reduces expression of the signature genes associated with hair induction in active DP. These results suggest that glucose metabolism is required for expression of signature genes associated with hair induction. This finding may be beneficial for establishing and maintaining of active DP to generate hair follicle in vitro.
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Dermis/metabolismo , Glucosa/metabolismo , Folículo Piloso/metabolismo , Histonas/metabolismo , Acetilación , Animales , Western Blotting , Supervivencia Celular/fisiología , Carbohidratos de la Dieta/metabolismo , Femenino , Glucólisis/fisiología , Metaanálisis como Asunto , Ratones Endogámicos C57BL , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
Nintedanib, a receptor tyrosine kinase (RTK) inhibitor has been developed as therapeutics for idiopathic pulmonary fibrosis and non-small lung cancer. We found that the expression levels of RTK, especially VEGFR1 is increased in skin biopsies of dermatitis patients from multiple independent datasets. Moreover, VEGFR1 is highly expressed by infiltrated cells in dermis from oxazolone (OXA) treated mice. Interestingly, nintedanib alleviates dermatitis symptom in OXA-induced animal model. Especially, levels of epidermis thickness, infiltrated immune cells including mast cells and eosinophils were decreased from mice cotreated with nintedanib and OXA compared with OXA treated mice. Moreover, serum IgE and Th2 cytokines including IL-4 and IL-13 were decreased by nintedanib treatment. These results suggest an evidence that nintedanib alleviates animal model of dermatitis.
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Dermatitis/tratamiento farmacológico , Dermatitis/metabolismo , Indoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Biomarcadores , Biopsia , Línea Celular , Supervivencia Celular , Dermatitis/etiología , Dermatitis/patología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Expresión Génica , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Ratones , Oxazolona/efectos adversos , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Receptor 1 de Factores de Crecimiento Endotelial Vascular/genética , Receptor 1 de Factores de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Glucose metabolism is a key metabolic pathway that orchestrates cellular homeostasis by generating ATP, nucleotides, and amino acids. Abnormal glucose signaling has been found in many diseases including cancers and inflammatory diseases. According to recent report, glycolysis contributes to pathogenesis of psoriasis and ablation of Glut1 attenuates animal models of psoriasis. While we were screening a molecular target for atopic dermatitis, we found the levels of glucose transporters including Glut1 (SLC2a1) and Glut3 (SLC2a3) are highly expressed in skin biopsies of dermatitis patients from multiple datasets. We demonstrated that administration of 2-deoxy-d-glucose (2DG) ameliorates animal models of 12-o-tetradecanoylphorbol-13-acetate (TPA) and oxazolone induced dermatitis using morphological and histological analysis. These results suggest that inhibition of glucose metabolism ameliorates dermatitis in animal models.
RESUMEN
HDAC2, one of the class I histone deacetylase regulates epigenetic landscape through histone modification. Because HDAC2 is overexpressed in many cancers, cancer therapeutics against HDAC2 have been developed. Here we show novel mechanism of HDAC2 regulation by E3 ligase RCHY1. We found inverse correlation RCHY1 and HDAC2 levels in tumor tissue from six independent dataset using meta-analysis. Ectopic expression of RCHY1 decreased the level of HDAC2 from cancer cells including p53 wildtype, mutant and null cells. In addition, HDAC2 was increased by RCHY1 knockdown. RCHY1 directly interacts with HDAC2. Ectopic expression of wild type but not RING mutant RCHY1 increased HDAC2 levels. These data provide an evidence that RCHY1 negatively regulates HDAC2.
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Histona Desacetilasa 2/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Células Cultivadas , Histona Desacetilasa 2/genética , Humanos , Ratones , Ratones DesnudosRESUMEN
HDAC3, one of the class I histone deacetylase modulates epigenetic landscape through histone modification. HDAC3 also interacts with non-histone proteins including p53 for deacetylation. Moreover, HDAC3 serves as a transcriptional repressor, interacting with NCor1/SMRT complex. Although HDAC3 plays a critical role for cellular homeostasis, regulatory mechanism of HDAC3 have been poorly understood. Here we report a novel regulatory mechanism of HDAC3 about its monoubiquitination and stabilization by Mdm2. HDAC3 levels were increased by ectopic expression of Mdm2 and decreased by Mdm2 ablation in various cell lines. We found that Mdm2 directly interacts with HDAC3 and induces HDAC3 protein levels without alteration of mRNA levels. Ectopic expression of wild type but not RING mutant of Mdm2 increased HDAC3 monoubiquitination. In addition, MdmX is beneficial for mdm2-mediated HDAC3 regulation. Ablation of Mdm2 and Mdm2/MdmX decreased cell migration along with the decrease of HDAC3 levels. These data provide an evidence that Mdm2 positively regulates HDAC3 monoubiquitination and stability.
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Histona Desacetilasas/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Movimiento Celular , Histona Desacetilasas/química , Humanos , Ratones , Procesamiento Proteico-Postraduccional , Estabilidad Proteica , UbiquitinaciónRESUMEN
Dermal papilla (DP) is a pivotal part of hair follicle, and the smaller size of the DP is related with the hair loss. In this study, we investigated the effect of titrated extract of Centella asiatica (TECA) on hair growth inductive property on 3D spheroid cultured human DP cells (HDP cells). Significantly increased effect of TECA on cell viability was only shown in 3D sphered HPD cells, not in 2D cultured HDP cells. Also, TECA treatment increased the sphere size of HDP cells. The luciferase activity of STAT reporter genes and the expression of STAT-targeted genes, SOCS1 and SOCS3, were significantly decreased. Also, TECA treatment increased the expression of the hair growth-related signature genes in 3D sphered HDP cells. Furthermore, TECA led to downregulation of the level of phosphorylated STAT proteins in 3D sphered HDP cells. Overall, TECA activates the potential of hair inductive capacity in HDP cells.
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Centella/química , Dermis/citología , Cabello/efectos de los fármacos , Cabello/crecimiento & desarrollo , Extractos Vegetales/farmacología , Transducción de Señal/efectos de los fármacos , Esferoides Celulares/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Esferoides Celulares/citología , Esferoides Celulares/metabolismoRESUMEN
Nutlin-3a is a non-genotoxic, p53-activating, MDM2 inhibitor being investigated as an anticancer agent. Although Nutlin-3a selectively antagonizes the ubiquitin E3 ligase activity of MDM2, its efficacy is not entirely regulated by MDM2 levels in cancer cells. Here, we report that the cytotoxic effects of Nutlin-3a are regulated by TRIAD1 via a positive feedback loop with p53. We found that Nutlin-3a enhanced TRIAD1 transcription in a p53-dependent manner. Using in silico analysis and promoter luciferase assays, we demonstrated that p53-mediated transcription of TRIAD1 is mediated by a p53 consensus sequence in the TRIAD1 promoter region. Silencing TRIAD1 expression in wild-type p53 (p53WT ) cancer cells suppressed Nutlin-3a-mediated p53 activation and p53 target gene expression. These effects were enhanced in TRIAD1-overexpressing p53WT cancer cells, but not in p53-deficient cancer cells. Furthermore, TRIAD1 knockdown significantly reduced the growth inhibitory and cytotoxic effects of Nutlin-3a in p53WT cancer cells, as demonstrated by cell viability assays, cell cycle analysis, clonogenic growth, and soft-agar colony forming assays. Together, these data indicate that TRIAD1 regulates Nutlin-3a-mediated p53 activation and the cytotoxic activity of Nutlin-3a. J. Cell. Biochem. 118: 1733-1740, 2017. © 2016 Wiley Periodicals, Inc.
Asunto(s)
Imidazoles/farmacología , Piperazinas/farmacología , Proteína p53 Supresora de Tumor/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Western Blotting , Ciclo Celular/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Línea Celular Tumoral , Humanos , Interferencia de ARN , ARN Interferente Pequeño/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteína p53 Supresora de Tumor/genética , Ubiquitina-Proteína Ligasas/genética , Proteínas de Unión al GTP rho/genética , Proteínas de Unión al GTP rho/metabolismoRESUMEN
As few prognostic markers and symptoms have been identified, ovarian cancer is typically diagnosed at an advanced stage, and a majority of patients will relapse and develop resistance to anticancer drugs such as paclitaxel. Musashi-2 (MSI2) is a regulator of gene translation and functions as an oncogenic protein and a marker of poor prognosis in various types of cancer. However, the biological and clinical significance of MSI2 in ovarian cancer remains unclear. Using a tissue microarray-based assay, we demonstrated that MSI2 was highly expressed in advanced, serous ovarian cancer tissues. In addition, MSI2-overexpressing ovarian cancer cells exhibited increased viability, proliferation and growth. We found that MSI2 was overexpressed in paclitaxel-resistant ovarian cancer SKOV3-TR cells but not in paclitaxel-sensitive cell lines. The loss of MSI2 expression in lentivirus-mediated stable MSI2 knockdown SKOV3-TR cells impaired paclitaxel resistance as determined using cell viability and apoptosis assays. In contrast, lentivirus-mediated MSI2 overexpression promoted the development of paclitaxel resistance in paclitaxel-sensitive ovarian cancer cells. The results of the present study are the first to demonstrate that MSI2 is a valuable marker of advanced, serous ovarian cancer and that MSI2 plays an important role in paclitaxel resistance.
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Biomarcadores de Tumor/metabolismo , Resistencia a Antineoplásicos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/patología , Paclitaxel/farmacología , Proteínas de Unión al ARN/metabolismo , Adenocarcinoma de Células Claras/tratamiento farmacológico , Adenocarcinoma de Células Claras/metabolismo , Adenocarcinoma de Células Claras/patología , Adenocarcinoma Mucinoso/tratamiento farmacológico , Adenocarcinoma Mucinoso/metabolismo , Adenocarcinoma Mucinoso/patología , Antineoplásicos Fitogénicos/farmacología , Apoptosis , Biomarcadores de Tumor/genética , Western Blotting , Proliferación Celular , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/metabolismo , Cistadenocarcinoma Seroso/patología , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/metabolismo , Neoplasias Endometriales/patología , Femenino , Humanos , Técnicas para Inmunoenzimas , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/metabolismo , Estadificación de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/metabolismo , Pronóstico , ARN Mensajero/genética , Proteínas de Unión al ARN/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células Tumorales CultivadasRESUMEN
BACKGROUND: Various health benefits have been attributed to Er-Miao-San (EMS), a traditional Chinese herbal formulation that contains equal amounts of cortex phellodendri (Phellodendron amurense Ruprecht) and rhizoma atractylodis (Atractylodes lancea D.C). However, its effect on the anti-inflammatory activity in human dermal fibroblasts (HDFs) and the mechanism underlying this effect are unknown. RESULTS: This study investigated the effects of EMS on TNF-α-induced MMP-1 expression in HDFs. Our data show that EMS inhibited TNF-α-induced MMP-1 expression in a concentration-dependent manner. Interestingly, EMS maintained IκB content without inhibiting the phosphorylation of MAPKs, which are well-established upstream kinases of NF-κB. Moreover, EMS reduced the level of nuclear p65 protein in HDFs. Luciferase assay revealed that EMS inhibits the transcriptional activity of NF-κB by stabilizing IκB. Our results show that EMS exerts its anti-inflammatory effect by inhibiting NF-κB-regulated genes such as IL-1ß and IL-8. Moreover, EMS effectively inhibited TNF-α-induced expression of MMP-1 via the NF-κB pathway. CONCLUSIONS: Taken together, our data suggest that EMS could potentially be used as an anti-inflammatory and anti-aging treatment.
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Envejecimiento/efectos de los fármacos , Dermis/citología , Medicamentos Herbarios Chinos/farmacología , Fibroblastos/efectos de los fármacos , Metaloproteinasa 1 de la Matriz/biosíntesis , Extractos Vegetales/farmacología , Antiinflamatorios/administración & dosificación , Línea Celular , Supervivencia Celular/efectos de los fármacos , Inducción Enzimática/efectos de los fármacos , Fibroblastos/enzimología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Interleucina-1beta/efectos de los fármacos , Interleucina-1beta/metabolismo , Interleucina-8/efectos de los fármacos , Interleucina-8/metabolismo , Proteínas Quinasas Activadas por Mitógenos/efectos de los fármacos , FN-kappa B/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
BACKGROUND: Various health benefits have been attributed to Er-Miao-San (EMS), a traditional Chinese herbal formulation that contains equal amounts of cortex phellodendri (Phellodendron amurense Ruprecht) and rhizoma atractylodis (Atractylodes lancea D.C). However, its effect on the anti-inflammatory activity in human dermal fibroblasts (HDFs) and the mechanism underlying this effect are unknown. RESULTS: This study investigated the effects of EMS on TNF-α-induced MMP-1 expression in HDFs. Our data show that EMS inhibited TNF-α-induced MMP-1 expression in a concentration-dependent manner. Interestingly, EMS maintained IkB content without inhibiting the phosphorylation of MAPKs, which are well-established upstream kinases of NF-kB. Moreover, EMS reduced the level of nuclear p65 protein in HDFs. Luciferase assay revealed that EMS inhibits the transcriptional activity of NF-kBbystabilizing IkB. Our results show that EMS exerts its anti-inflammatory effect by inhibiting NF-kB-regulated genes such as IL-1ß and IL-8. Moreover, EMS effectively inhibited TNF-α-induced expression of MMP-1 via the NF-kBpathway. CONCLUSIONS: Taken together, our data suggest that EMS could potentially be used as an anti-inflammatory and anti-aging treatment.
Asunto(s)
Humanos , Envejecimiento/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Extractos Vegetales/farmacología , Dermis/citología , Metaloproteinasa 1 de la Matriz/biosíntesis , Fibroblastos/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Inducción Enzimática/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Interleucina-8/efectos de los fármacos , Interleucina-8/metabolismo , FN-kappa B/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Proteínas Quinasas Activadas por Mitógenos/efectos de los fármacos , Interleucina-1beta/efectos de los fármacos , Interleucina-1beta/metabolismo , Reacción en Cadena en Tiempo Real de la Polimerasa , Fibroblastos/enzimología , Antiinflamatorios/administración & dosificaciónRESUMEN
Non-small cell lung cancer (NSCLC) is the most deadly type of cancer worldwide. Although a number of therapies are used in NSCLC treatment, their therapeutic efficacy remains low. Lenalidomide was originally approved for use in patients with myelodysplastic syndromes, which are associated with 5q deletions, and multiple myeloma. Recently, lenalidomide was investigated as a new NSCLC treatment, and it exerted anticancer effects. However, the primary cellular mechanism of its effects in NSCLC is largely unknown. Therefore, we attempted to elucidate a molecular portrait of lenalidomide-mediated cellular events in NSCLC. Lenalidomide reduced the viability of several NSCLC cell lines in a concentration-dependent manner. In addition, array-based gene expression analysis revealed that lenalidomide regulated the expression of several genes associated with cell survival, apoptosis and development, including BH3-interacting domain death agonist (BID), v-fos FBJ murine osteosarcoma viral oncogene homolog (FOS) and NK2 homeobox1 (NKX2-1). BID and FOS, which are known apoptosis activators, were upregulated by lenalidomide treatment, whereas NKX2-1, which is used as an immunohistochemistry marker for NSCLC, was downregulated. These results provide evidence that lenalidomide directly induces antiproliferative effects by altering the expression of genes associated with cell proliferation and apoptosis.
RESUMEN
Hypoxia is a common feature of tumors that occurs across a wide variety of malignancies. Multiple myeloma is an incurable malignant disorder of plasma cells in the bone marrow. Although bone marrow hypoxia is crucial for normal hematopoiesis, the effect of hypoxia on multiple myeloma is poorly understood. In this study, we demonstrated that cobalt chloride (CoCl2)-mediated hypoxia decreased cell viability and altered gene expression in U266 human multiple myeloma cells. CoCl2 induced the loss of cell viability in a concentration-dependent manner. In addition, FACS analysis revealed that the loss of cell viability was related to apoptosis. Using microarray analysis, we identified mRNA expression profile changes in response to CoCl2 treatment in U266 cells. Four hundred and fifty-two mRNAs exhibited >2-fold changes in expression in CoCl2-treated U266 cells compared to their expression in control cells. A follow-up bioinformatics study revealed that a great number of genes with altered expression were involved in apoptosis, cell cycle, transcription and development. In conclusion, these results provide novel evidence that CoCl2-mediated hypoxia affects the expression profiles of genes that are functionally related to apoptosis and angiogenesis in U266 multiple myeloma cells.
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Puntos de Control del Ciclo Celular/efectos de los fármacos , Cobalto/farmacología , Expresión Génica/efectos de los fármacos , Hipoxia de la Célula , Línea Celular Tumoral , Supervivencia Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Mieloma Múltiple , Análisis de Secuencia por Matrices de Oligonucleótidos , Transcriptoma/efectos de los fármacosRESUMEN
Cytochrome P450 1A1 (CYP1A1) is a member of the cytochrome p450 enzyme family, which is involved in the metabolisms of carcinogenic metabolites, such as benzo(a)pyrene. In this study, we identified miR-892a as a negative regulator of CYP1A1 expression. Luciferase assays revealed a sequence in the 3'-untranslated region of CYP1A1 that displayed a perfect match with miR-892a, and revealed that this sequence was a specific miR-892a target site. The overexpression of miR892a inhibited the expression of the CYP1A1 protein, and the miR892a antagonist increased CYP1A1 expression. Of note, benzo(a)pyrene, a major inducer of CYP1A1 transcription, decreased the expression of miR-892a. Moreover, the miR-892a-induced CYP1A1 repression inhibited the benzo(a)pyrene-mediated decrease in cell viability. These data provide insight into the CYP1A1 regulatory network.